rabbit haemorrhagic disease: field epidemiology and the

IntroductionIn 1984, an unknown disease was reported in the People’sRepublic of China among Angora rabbits which had beenrecently imported from the German Democratic Republic (28).Within a few months, the disease had spread widely throughcommercial rabbitries in the People’s Republic of China (59)and had also reached the Republic of Korea (41). Investigators

in the People’s Republic of China rapidly developed aninactivated vaccine, using livers of infected rabbits, to controlthe disease (25). Nevertheless, a new unknown disease, initiallynamed ‘Malattia-X’, appeared in domestic rabbits in Italy in1986 (9), leading to the deaths of millions of domestic rabbits.This new disease soon appeared in other countries in Europe(34), and in 1987-1988, a link was established with the viralhaemorrhagic disease of rabbits in the People’s Republic ofChina. Research on this new disease was rapidly initiated in

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SummaryRabbit haemorrhagic disease (RHD) has become established in wild rabbitpopulations throughout Western Europe, Australia and New Zealand. Theabundance of wild rabbits has been significantly reduced, particularly in drierareas of southern Spain, inland Australia and South Island New Zealand. Adetailed knowledge of the epidemiology of RHD is essential for the managementof the disease in natural rabbit populations, either to rebuild or to controlpopulations. When RHD first spread among naïve wild rabbits, epidemiologicalstudies provided unique information on the rate of spread, the possible role ofinsect vectors in transmission, and the correlation between the impact of diseaseon populations and climatic variables. Current research shows a consistentpattern of epidemiology between Europe and Australasia. Typically, the mostsevere epizootics of RHD occur among young sub-adult rabbits which have lostage-related resilience and maternal antibodies. However, the timing of theseoutbreaks reflects climatic variables that determine the breeding season of therabbits and the periods when RHD virus (RDHV) is most likely to persist andspread. Further factors that may complicate epidemiology include the possibility that non-pathogenic RHDV-like viruses are present in natural rabbit populations.Additionally, the question of how the virus persists from year to year remainsunresolved; persistance in carrier rabbits is a possibility. Understanding of theepidemiology of RHD is now sufficiently advanced to consider the possibility ofmanipulating rabbit populations to alter the epidemiological pattern of RHD andthereby maximise or minimise the mortality caused by the disease. Altering theepidemiology of RHD in this manner would assist the management of wild rabbitpopulations either for conservation or pest control purposes.

KeywordsCaliciviruses – Control – Epidemiology – Rabbit haemorrhagic disease – Rabbits –Wildlife.

Rabbit haemorrhagic disease: field epidemiology and the management of wild rabbit populations

B.D. Cooke

Commonwealth Scientific and Industrial Research Organisation (CSIRO) Sustainable Ecosystems, G.P.O. Box 284, Canberra ACT 2601, Australia

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Europe, because of the commercial value of the rabbits for meatand fur production.

Typically, rabbits died within 24 h-48 h of infection and showedfew outward signs of disease, although bloody mucousdischarge from the nose was occasionally observed. Atnecropsy, a discoloured liver, large spleen and smallhaemorrhages on the surface of organs such as the kidneys wereapparent. Major haemorrhages were often found in the lungs,and the trachea showed hyperaemia and contained frothyblood-tinged mucous.

The causative agent of the disease was subsequently establishedto be a calicivirus specific to the European rabbit (Oryctolaguscuniculus) (40). Similar to other caliciviruses, rabbithaemorrhagic disease virus (RHDV), as the agent has eventuallybecome known, was found to be a non-enveloped ribonucleicacid (RNA) virus with an icosahedral capsid of 30 nm indiameter, comprised of 180 protein molecules. However, thearrangement of the genome differs from that of other groups ofcaliciviruses to the extent that the virus is now classified alongwith European brown hare syndrome virus in a separate groupknown as lagoviruses (23).

By 1988, rabbit haemorrhagic disease (RHD) occurred not onlyin Europe, but had also been reported among domestic rabbitsin the Russian Federation, in the Middle East and parts ofAfrica, and in Cuba, Mexico and India (34). The disease wasalmost certainly spread by trade in rabbit meat and fur, or byshipment of consignments of infected rabbits.

In Europe, the virus rapidly spread from domestic to wildrabbits and was soon well established. The first cases of RHD inthe wild were reported in Spain in June and July of 1988, andresulted in high mortality. Soon afterwards, the disease wasreported in France (42). As the wild rabbit is an importantgame species in both countries, interest in the disease wasintense. However, the spread of RHD also raised seriousconservation concerns. The rabbit is an important element ofMediterranean shrubland ecosystems, both as a grazing animaland because rabbits support a number of endangered predatorssuch as the Spanish lynx (Lynx pardina) and the imperial Eagle(Aquila adalberti). With the confirmation of RHD in wild rabbitsin Scandinavia by January 1990 (47, 19) and in Great Britainby August 1994 (54), RHD had clearly become well establishedin wild rabbit populations throughout western Europe.

The data on the spread of RHD are broadly supported bynucleotide differences in forty-four RHDV samples collectedacross Europe at this time (38). A phylogenetic tree based onthose samples corresponds well, even though RHD in Spainand France appears to have originated from separateimportations from the initial outbreak in Italy.

The impact of RHD on wild rabbit populations in Europe wasfollowed with great interest in Australia and New Zealandwhere wild rabbits had been introduced during the 19th

Century and were widely regarded as pests of agriculture and athreat to conservation of native plants and wildlife. In 1991,RHDV was imported into Australia and maintained in strictquarantine in the Australian Animal Health Laboratory whiletests were performed to establish the safety and efficacy of thevirus if used as a biological control agent. Included in thistesting were host specificity trials which demonstrated that thevirus caused no disease in any of the native mammals or birdstested (27). In 1995, more quarantined tests began on WardangIsland, off the coast of South Australia, to determine whetherthe virus would spread effectively among wild rabbits under thedry conditions typical of much of southern Australia. However,despite painstaking precautions to manage the quarantinefacility (18), the virus demonstrated its pre-adaptation to theenvironment of Australia by spreading beyond the quarantinefences, crossing several kilometres of sea and rapidly spreadinginto dense rabbit populations in inland Australia.

The escape from Wardang Island and the rapid initial spread ofRHDV across the continent caused both amazement and alarm,but the virus has subsequently proved to be an extremely usefulbiological control agent against the introduced rabbit. Rabbithaemorrhagic disease has now been established in Australia forover six years and has substantially reduced the abundance ofrabbits.

Although the New Zealand Government maintained extensiveinterest and provided financial support for the investigationsinto the use of RHD for the biological control of rabbits inAustralia, the authorities nevertheless decided not to use RHDVin New Zealand. However, farmers in areas where rabbits werea problem took the matter into their own hands. On 23 August1997, RHD was confirmed on a farm in Central Otago on theSouth Island (53). Containment was attempted, but the viruswas found to be present on many farms, and farmers werespreading the virus deliberately by treating carrot bait withhomogenates of livers taken from rabbits which had died fromthe disease. In September 1997, the New Zealand Governmentagreed to legalise the use of RHDV for biological control andsupplies of purified RHDV have since been made available forthat purpose.

This review discusses the principal results obtained from fieldepidemiological studies on wild rabbits undertaken in Europe,Australia and New Zealand. Information has been derived notonly from the initial spread of the virus, but also fromcontinuing field investigations and laboratory studies aimed atextending knowledge of the disease. However, byconcentrating on the main epidemiological processes, asummary of information is provided which should form a basisfor further management of RHD in rabbits, whether directed atrabbit conservation or population control.

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Initial spread of rabbithaemorrhagic disease in wildrabbitsEuropeIn Europe, the initial spread of RHD to wild rabbits was linkedso closely with the spread among commercial rabbitries thatobtaining insights into epidemiology through unravelling thekey factors involved is extremely unlikely. Disposal of wastefrom rabbitries and the use of fresh cut herbage to feeddomestic rabbits no doubt provided routes for spreadingRHDV in both directions between wild and captive rabbits.Nevertheless, observations in domestic rabbits clearlyestablished the importance of transmission through directcontact and fomites, and seasonal patterns of epidemics wereobserved, indicating that climatic variables might be important.Exploration of the possibility of insect transmission revealedthat flies of the genus Phormia transmitted the virus, with veryfew viral particles required to infect a rabbit via the conjunctiva(21). The involvement of seabirds in RHDV transmission innorthern Europe was the subject of much conjecture (12, 20,32), particularly when RHD appeared on off-shore islands.

Once RHD became established in wild rabbit populations inEurope, a number of studies recorded the initial impact. Anearly outbreak was observed in the province of Almería in aridsouth-eastern Spain in June 1988 (46). Dead rabbits werepresent in such abundance that many were left untouched byscavengers (R. Soriguer and B.D. Cooke, unpublished data).Subsequent spread of the disease was well documented. InDecember 1988, the disease was detected in the province ofMurcia, to the north of Almería. Serological studies performedat three-monthly intervals on live-captured rabbits revealed thatmany of the surviving rabbits, both adult and sub-adult, carriedantibodies detectable by haemagglutination inhibition (HI)tests (L. León-Vizcaíno, personal communication). During thefollowing year, confirmation was obtained that some veryyoung rabbits carried antibodies against RHD, but these wereconsidered to be temporary maternal antibodies because allsubadults were seronegative. Nevertheless, the proportion ofrabbits carrying antibodies declined as more and more youngjoined the adult population. By January 1990, no seropositiverabbits were found, but in May 1990, seropositive rabbits wereagain detected, indicating that a second disease outbreak hadoccurred.

The spread of RHD across the province of Murcia was irregular,but a broad front could be recognised with the diseasespreading at a rate of approximately 15 km per month. León-Vizcaíno (personal communication) took advantage of thisirregularity to compare an RHD-affected rabbit population nearBullas with an RHD-free population nearby. Using transect

counts to follow changes in rabbit numbers and detectcadavers, the study showed that from mid-June to mid-July1990, RHD reduced rabbit numbers by almost 50% incomparison with the uninfected site. Haemagglutination (HA)tests were used to confirm RHD in cadavers found in theaffected area and HI tests were used to detect antibodies inthose rabbits that survived. Neither dead rabbits nor rabbitswith antibodies were detected on the control site.

At approximately the same time, the spread of RHD wasfollowed even further north through Alicante, an adjoiningcoastal province (43). Again RHD spread at approximately 15 km per month, from an outbreak in the south which beganin the autumn of 1988 (October) and eventually merged witha second disease outbreak towards the north of the province.Not all rabbit populations were affected as the disease spread;some hunting reserves remained untouched. Furthermore, asharp decline in disease activity occurred at the start of summer.The number of rabbits shot by hunters within the provincedeclined between 1988 and 1989, but recovered to someextent in 1990. Counting rabbits along standardised transectsdemonstrated that on one site the peak counts in June each yearfell from 21.1 rabbits/km in 1988 to 5.2 rabbits/km in 1989,then recovered to 21.2 rabbits/km in 1990. Following theinitial outbreaks, less intensive, localised outbreaks of RHDoccurred in the late winter (February-March) of 1990 and inthe spring (April-May) of 1991 (V. Peiró, personalcommunication).

Despite a relatively rapid transmission through Almería, Murciaand Alicante, RHD nevertheless took some years to reach allwild rabbit populations across the Iberian Peninsula. Eventhough RHD had already been reported from Portugal in 1989(1), the initial spread of RHD through Doñana National Park insouth-western Spain only occurred in March-May 1990. Radio-collars were fitted to rabbits to follow the spread of the diseasein the national park and a death rate of 55% was recorded inadult rabbits with both sexes being equally affected. Hightemperatures in the area in late spring and summer werethought to have curtailed the epizootic. However, the epizooticof RHD at Doñana did not appear to be associated withseasonally high mosquito numbers and researchers concludedthat vectors did not play a decisive role in transmission (55).

Five years were required for RHD to reach most wild rabbitpopulations in Spain (51, 56). A similar picture was observedin France where the disease first appeared in 1989. Recurrentoutbreaks of RHD soon occurred among wild rabbits in theCarmargue, Vaucluse and Hérault in the south of France (46)and the incidence of the disease was carefully monitored morebroadly across France from 1994 onwards (2, 4, 33). However,not until 1995 was the first outbreak of RHD seen at theChèvreloup arboretum, near Paris, among rabbits monitoredsince 1989 (31). The Chèvreloup rabbit population declined to12% of the initial level over the course of a year.

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The initial impact of RHD on wild rabbit populations in Europeappears to have been strongly influenced by geography andclimate. The greatest recorded declines in rabbit abundancewere in Spain, Portugal and France, whereas the virus reducedrabbit populations less severely in Great Britain and othercountries of northern Europe.

Spain is the only country where a major effort was made toassess the broad impact of RHD on rabbit populations (5).Hunters were interviewed to determine how rabbit numbershad changed since the arrival of RHD, then a nearby site with arabbit population typical of the general area was visited and theassessments of post-RHD rabbit numbers as supplied by thehunters were standardised against quantitative field data. Foreach site, the relative rabbit density was estimated fromsightings of rabbits and other signs such as warrens, diggings ordung along a 4-km transect. Data from 311 sites across Spainwere compiled and climatic data, soil types and land use wasalso collated before considering the questionnaire results.

Most hunters interviewed considered that the disease recurredannually with most outbreaks in winter or spring. It wasconcluded that, five years after the arrival of RHD, rabbitpopulations across Spain were being maintained at slightly lessthan 50% of their former levels. Nevertheless, some rabbitpopulations made better recoveries than others. In areas whichwere most favourable for rabbits, generally warmer sites withannual precipitation of approximately 450 mm-500 mm, rabbitnumbers had a small but significant tendency to recover.However, in areas which were generally unfavourable torabbits, populations had a strong propensity to remain low.Management of rabbit populations, often involving the controlof predators, was also thought to be important in facilitatingrecovery of rabbit numbers.

In contrast, RHD required a long time to become established inGreat Britain and has an uneven distribution. Even before RHDbecame widespread (13), sera from wild rabbits throughoutGreat Britain reacted in HI tests that usually indicatedantibodies to RHD. Twenty-two of these seropositive rabbitswere challenged with virulent RHDV and all survived. Rabbitsthroughout France also carried antibodies which reacted inRHD enzyme-linked immunosorbent assays (ELISAs), even onislands where RHD had never been detected or suspected (32).The presence of these antibodies in Great Britain and Francenow seems explicable given the isolation of a non-pathogenicrabbit calicivirus (RCV) from domestic rabbits (11). Similarrabbit caliciviruses may well be present among wild rabbits,and arguably, these probably provided the precursors for RCVand virulent RHDV in domestic rabbits (18).

Clearly, several possible explanations exist for the apparentdifferences between the impact of RHD in southern andnorthern Europe, and one possibility is the presence of a pre-existing RHDV-like virus that effectively immunises rabbits

against virulent RHDV. This theory needs to be substantiated byisolation of the putative virus.

Australia and New ZealandIn contrast to the situation in Europe, the domestic rabbitindustry in Australia is small and was not associated with theinitial spread of RHDV. Furthermore, research into theepidemiology of RHD in wild rabbits was central for use of thevirus as a biological control agent. Consequently, researcherswere better prepared to monitor the spread of disease (14, 22)and considerably more information was gathered during theinitial spread of RHD through the naïve rabbit population thanwas the case in Europe.

Although pen-trials on Wardang Island were curtailed by theescape of the virus to the mainland, some important resultswere obtained, especially when viewed retrospectively. Thedisease did not spread as easily within natural warrens as hadbeen imagined from small-scale laboratory trials. This wasprobably due to the precautionary removal of rabbit carcassesfrom experimental pens within 24 h of death. These werereadily located and retrieved even from deep rabbit burrowsusing signals from the radio-collars fitted to each rabbit.Nevertheless, the highest rate of spread under experimentalconditions was observed in June and July, the coolest monthsof the Southern Hemisphere winter, now regarded as animportant time for field epizootics. By following the timebetween deaths of rabbits in experimentally infectedpopulations and reintroducing rabbits into warrens formerlyinhabited by infected rabbits, researchers established thatinfectious virus probably persisted in warrens for a relativelyshort time (i.e. several days rather than several weeks).

Experimentally infected rabbits died on average 42 h afterinfection. None showed behavioural changes untilapproximately 12 h before death, and some cadavers retainedfresh grass in their mouths indicating that they had been eatingshortly before they died. All adult rabbits that were infectedexperimentally died and approximately 75% of cadavers werefound below ground in the burrows.

Insect vectors were of obvious interest in understanding theescape of the virus from the quarantine enclosure on WardangIsland, and bushflies (Musca vetustissima) and some of the largerblowflies (e.g. Caliphora dubia) were rapidly identified aspotential mechanical vectors of the virus. Analysis of climaticdata from the island and adjacent mainland was used toestimate times and directions of possible dispersal of the viruson insects (57). These estimates suggest that insects could havespread the virus from Wardang Island to the mainland underthe weather conditions that prevailed between 12 and14 October 1995. The trajectories of wind-borne insects in thatperiod agree with the distribution of infected rabbitssubsequently detected on the mainland (18). Many species of


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flies, mosquitoes and fleas readily become contaminated withRHDV in the field, and blowflies can retain virus in the gut forup to nine days after feeding on RHDV-infected rabbit liver.Furthermore, a single fresh fly-spot from these flies, containingan estimated 2-3 times the median lethal dose (LD50) of thevirus, was sufficient to infect a rabbit, if ingested (3).

Blowflies are not the only insects capable of transmitting RHDV;the rabbit fleas Spilopsyllus cuniculi and Xenopsylla cunicularis,and the mosquito Culex annulirostris can transmit RHDV underlaboratory conditions (27).

Data collected as RHD spread across mainland Australiaprovided further important insights into the likelyepidemiology of the disease. Even in remote parts of Australiawhere deliberate human transfer was unlikely, RHDV spread farmore rapidly than could be explained by rabbit to rabbit spread(26). Even the spread by predatory mammals such as foxes,known to excrete viable virus in their faeces after eating infectedrabbits (50), provides an inadequate explanation. Again thisindicated that flying insects were an important vector, at leastduring initial disease establishment. Data from Australiatherefore point to a role for insects in the transmission of RHDVthat was not apparent in the studies from Europe. Nevertheless,flies or mosquitoes might only be involved in occasional long-distance spread of the disease and contact transmission isprobably the principal route of infection for maintaining RHDoutbreaks in local populations.

As implied from observations in Europe, the initial rate ofspread of RHDV is also influenced by the season (52). Insummer, few new disease foci were observed in comparison tothose recorded from autumn or spring (26). Recurrence ofRHD a year after the initial arrival of the disease alsoemphasised regional and seasonal patterns of mortality anddifferences in the efficacy of the disease between hot, dry areasand cool, wet areas. This may reflect differences in virusbehaviour or survival because ambient temperature has nodirect effect on the course of RHD in infected rabbits (15).

Field studies in many localities across Australia revealed thatregional differences in the impact of RHD persisted well afterinitial establishment of the disease. At some arid sites, rabbitnumbers fell to less than 15% of former levels and haveremained low (6, 16, 35). At other sites, the decline in rabbitnumbers was more gradual, continuing over some years, whileelsewhere, populations have recovered from an initial declineor apparently absorbed any mortality caused by RHD withoutany population change (49).

Analysis of data from eighty-two sites across Australia, forwhich pre- and post-RHD transect counts of rabbits wereavailable, showed that mortality caused by the disease wasstrongly influenced by climate (37). The initial impact of RHD

was higher in arid and semi-arid areas of inland Australia thanin cooler humid regions of the Eastern Highlands and the coast.Subsequent principal component analysis of the same data canbe interpreted as indicating that strong climatic componentsdrive these regional variations in epidemiology (R. Henzell,personal communication). The initial impact of RHD appearsto have been greatest in high-density populations once climaticvariables are taken into account. Analysis of data relating to thedeliberate release of RHDV as a biological control agent in NewSouth Wales showed a strong association between the presenceof heavy infestations of rabbit fleas (Spilopsyllus cuniculi),breeding in rabbits and RHD. Low temperatures also promotedoutbreaks (30).

In New Zealand, where RHDV was being deliberatelytransmitted on baits spread for rabbits to eat, comparisons weremade between the epidemiology of RHD in a baited area andanother site where the disease spread naturally (42). At the sitewhere RHDV was deliberately spread, the death rate peakedthree days after baits were spread. However, where the diseasespread naturally, the peak death rate was observed at abouttwenty days, and some fresh carcasses were found for up toeighty days. According to estimates, on the site where RHD wasdeliberately spread, 66% of rabbits apparently died, 25% werechallenged with RHDV but survived, and 9% apparently didnot ingest infectious baits. Where the disease spread naturally,66% of rabbits also died, 12% survived challenge and 22% didnot become infected.

The spread of RHDV in New Zealand was broadly monitoredusing serological tests of rabbit serum samples from thirteensites, and a positive correlation was found between the survivalrate of rabbits during epizootics and the subsequent levels ofantibodies observed in the remaining rabbits. The widespreaduse of RHDV-contaminated baits, with little control of theviability or virulence of the virus, could have resulted inprotective immunisation of some rabbits (39).

The role of insect vectors, mainly blowflies (Calliphoridae) wasalso investigated in New Zealand (24). Although flies wereconsidered to be likely vectors, no clear relationships existedwhich indicated any species as being of key importance.Interestingly, Lucilia sericata and Calliphora vicina, bothintroduced from Europe, were among the four species onwhich RHDV was regularly detected by reverse transcriptasepolymerase chain reaction (RT-PCR).

As observed in Europe, an increasing body of evidence suggeststhat other RHDV-like viruses were present in rabbit populationsin Australia and New Zealand when RHDV first spread. Testingof rabbit sera collected from south-eastern Australia some yearsbefore the introduction of RHDV into Australia revealed thatmany rabbits appeared to have antibodies to a putative RHDV-like virus (44). Furthermore, recombinant virus-like particles


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(rVLPs) expressed in baculovirus have been used in ELISAs todetect antibodies in sera collected from wild rabbits ahead ofthe arrival of RHD (36). This work not only demonstrated thatmany rabbits had pre-existing antibodies, but also providedevidence that high titres of those antibodies protected rabbitsagainst fatal RHD. The fact that antibodies to the putativeRHDV-like virus occur at higher titres in wet areas compared todry regions of southern Australia (17), might offer oneexplanation for the reduced effectiveness of RHD in many highrainfall regions as the disease first spread.

In New Zealand, rabbit sera collected before the spread ofRHDV showed significant reactivity in competition ELISAsdeveloped to detect RHDV antibodies (39). Nevertheless,although the pre-existing antibodies were widespread, up to90% of wild rabbits died from RHD in some regions (29). Thus,the pre-existing antibodies may not have conferred significantprotection against RHD.

Epidemiology since initialestablishment of rabbithaemorrhagic diseaseThe initial spread of RHD through wild rabbit populations wasa new phenomenon. Although some populations may have hadprotection from pre-existing antibodies produced by related,non-pathogenic viruses, many populations were essentiallynaïve and highly susceptible. Mortality rates were highespecially among adult rabbits. Nevertheless, field data showedthat young rabbits were less likely to die from infection thanadults (55), a fact well known from investigations usinglaboratory rabbits. Approximately 40% of young rabbitsbetween five and eight weeks of age survive experimentalinoculation with RHDV, whereas only 10% of rabbits over nineweeks of age survive (34).

Young rabbits also acquire protection against RHD in the formof maternal antibodies. Such antibodies were observed in Spainin early 1989, as soon as survivors from the first RHD outbreakresumed breeding (L. León-Vizcaíno, personalcommunication). The presence of maternal antibodies in wildrabbits has since been confirmed (16). In female rabbitspreviously exposed to RHDV, immunoglobulin G (IgG)antibodies are readily transferred to the young across theplacenta, and antibody titres in late-stage embryos approximatethose of the mother (B.D. Cooke, unpublished data).

Without doubt, the best epidemiological study of RHD in wildrabbits in Europe was undertaken by C. Calvete and colleagueswho worked in the semi-arid Ebro valley near Zaragoza innorth-eastern Spain (7, 8). Using radio-tagged rabbits, the fateof individual rabbits was followed during successive outbreaksof RHD over four years. Epizootics of RHD generally lasted for

four to five weeks and occurred at variable times in the wintermonths from October to early March. By late spring (earlyMay), the disease became less apparent. The disease spreadunevenly through the population, affecting some social groupsof rabbits but not others living in close proximity. Outbreaksearly in the winter usually affected seronegative young adultsand often lead to the death of suckling young as a consequence.

Outbreaks later in the season principally affected juvenileswhich had lost age-related resilience and maternal antibodyprotection and an estimated 50% of juvenile rabbits died.Approximately 50% of the adult rabbit population carriedantibodies against RHDV, although this percentage rose withthe passage of disease through the population.

Calvete and Estrada (8) recognised the importance of theresilience of kittens in epidemiology, whether age-related oracquired from the mother, in enabling rabbit populations towithstand RHD. These authors argued that mortality from RHDshould increase with increasing population density, due toincreased contact between rabbits. However, high populationdensities would also lead to a reduction in the median age atinfection towards the age at which young rabbits still have age-specific or maternal antibody protection and can surviveinfection. This means that the effect of RHD on the populationas a whole is reduced because sufficient numbers of youngrabbits survive to maintain the basic breeding population. Thiswould explain the current situation in Spain where some low-density rabbit populations show no sign of recovery whiledense populations seem scarcely affected by RHD.

This general model requires further testing. Nevertheless, fielddata from Australia appear to support the general patternexcept that the epidemiological process occurs in sharplydefined periods. This is because climatic factors not only causevariation in the rate of spread of the virus but also make rabbitbreeding strongly seasonal. On this basis, it is possible thatclimatic factors which support high rabbit densities also directlyinfluence other variables such as the timing and duration ofrabbit breeding, and indirectly, the mortality caused by RHD.

Epidemiological studies in Australia have benefited greatly fromthe use of ELISA methods developed in Italy for the veterinarydiagnosis of RHD in domestic rabbits (10, 11). A goodunderstanding of the serological changes associated withinfection by RHDV has been achieved using ELISA to discernand quantify the antibody isotypes IgG, IgA and IgM (16). Thedata show that some rabbits may maintain traces of maternalantibodies in the field (exclusively IgG isotype) for at leasttwelve weeks. The protective effects of age-related resilienceand maternal antibodies have been analysed experimentally(T. Robinson, personal communication), confirming that age-specific resilience lasts for approximately five weeks, butdepending on the titre of the mother, maternal antibodiesreduce the risk of mortality in older animals up to twelve weeksof age.


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Those rabbit kittens that survive RHD while protected by bothage-specific resilience and maternal antibodies often showrelatively low antibody titres. In contrast, rabbits which havelost all trace of maternal antibodies, but are lucky enough tosurvive infection as sub-adults, have IgG antibody titresapproximately ten times higher. Rabbits with high antibodytitre are also likely to respond more acutely on re-exposure toRHDV, particularly following oral re-exposure which producesa strong mucosal (IgA) response (B.D. Cooke and J. Merchant,unpublished findings).

Antibody titres in rabbits which survive RHD generally declinewith time following infection, but in the field, antibodies arefrequently boosted as a result of re-expose to RHDV (16). BothIgG antibody isotypes and IgA isotypes increase and slowlybuild up in older rabbits. This potentially influences the levelsof maternal antibodies in the progeny of rabbits repeatedlyexposed to RHDV.

Apart from age-related resilience to infection or protectionafforded by maternal antibodies, young rabbits are also clearlyless prone to infection with RHDV than adults. When RHD firstescaped from experimental pens on Wardang Island, and beganspreading through fully susceptible rabbits, a higher proportionof adult rabbits than young became infected. It has recentlybeen demonstrated that RHDV binds to the common ABHantigens found on the surface of many mammalian cells (48).This explains why the agglutination of human red blood cellsprovides a basis for the common HA and HI tests used to detectRHDV and antibodies to RHDV. However, in the rabbit, theseantigens are found on the mucosal cells of the gut and upperrespiratory tract and only begin to become fully functionalwhen the rabbits reach approximately six weeks of age. Thispattern of development of mucosal ABH antigens has beenconfirmed from inner cheek swabs collected from wild rabbitsin both France and Australia (J. Le Pendu, S. Marchandeau andB.D. Cooke, unpublished data).

At Gum Creek in semi-arid South Australia, outbreaks ofRHDV usually occur in autumn or early winter (May-July),around the time that rabbits begin breeding. Young adultrabbits which have lost maternal antibodies over the summerare principally affected and an estimated 87% of those affecteddie. Kittens from the first litters of the breeding season may alsobe affected at that time, although RHDV does not necessarilypersist to affect siblings born later in the season. The spread ofRHD among rabbit kittens appears to occur readily only wheninfected adults are present; the disease does not spread wellamongst young rabbits alone. As a consequence, the late-bornyoung lose the last of their maternal antibody protection andbecome fully susceptible by mid-summer, while virus activityremains low. However, these individuals are prime candidatesfor infection as the weather cools and the next breeding seasonbegins.

Recruitment into the adult breeding population at Gum Creektherefore depends heavily on the proportion of young rabbits

that contract RHDV when very young and are able to surviveinfection. Unless RHD occurs widely among young rabbitsduring spring (August-November) when over 80% of rabbitsare born, too few young rabbits persist to maintain the breedingpopulation. Although the Gum Creek rabbit population wasreduced by over 90% when RHDV first spread in 1995 (35),the population has further declined over the last few years, toapproximately three to four rabbits per spotlight km, as theimmune adult population has dwindled for lack of recruitment.On the basis of the model by Calvete and Estrada (8), it couldbe argued that rabbit density in this location has fallen belowthe point at which the disease spreads sufficiently well to affectsignificant numbers of young rabbits. Nevertheless, the effectsof season are difficult to separate in these interactions. Years ofhigh rainfall might not only see an increase in rabbit breedingand rabbit density, but may also facilitate the persistence andspread of the virus.

In a contrasting study, near Bacchus Marsh, Victoria, Australia(S. McPhee and B.D. Cooke, unpublished data), fewseronegative rabbits are observed, the implication being thatmost must be exposed to RHDV while natural resilience andmaternal antibodies are still present. However, interpretation ofdata from this population has the added complication thatmany rabbits have antibody profiles indicating that a putativeRHDV-like virus is also widespread and may provide evengreater protection against RHDV. The Bacchus Marshpopulation declined by only 40% when RHD arrived in 1996,but the rabbit population rapidly recovered and has sincemaintained itself at a relatively high density, as judged fromnight-time counts (approximately fifty rabbits per spotlightkm).

Rabbit haemorrhagic disease virus clearly persists from year toyear, although the mechanism for this persistence is not fullyunderstood. In some populations, despite sharp outbreaksoccurring in mid-winter, sporadic cases of RHD can beobserved among sub-adult rabbits at almost any time.Furthermore, the virus is known to persist for at leastthree weeks in carcasses (58), thus the regular recurrence ofdisease as breeding begins may indicate the persistence of virusin cadavers which are disturbed as nesting chambers arerenovated (8). Nevertheless, contact between susceptiblerabbits and cadavers is probably not confined to suchsituations, and it has been argued that some rabbits may act ascarriers of RHDV and that under stressful conditions, virulentvirus might be shed (7, 30). Indeed, both viral RNA and the 60-kDa coat protein from RHDV are recoverable from wildrabbits which have previously been exposed to RHDV(C. Musso and I. Lugton, personal communication). This RNAand viral protein has been detected in tonsils, Peyer’s patchesand the blood. Nevertheless, observations reveal that in somerabbit populations RHD does not occur each year. This suggeststhat carriers of virus may readily shed virus only under severestress, or that effective carriers are not commonly found.Movement of rabbits or vectors may also be necessary tomaintain RHD.


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Further researchIn addition to considering the interesting possibility that RHDVmay be a persistent virus in some rabbits, further researchshould be undertaken regarding matters of more immediatepractical interest. In particular, confirmation of the existence ofthe putative RHDV-like viruses is important; isolation andexperimental demonstration of transmissibility should beperformed. Furthermore, studies should confirm whetherantibodies to these putative RHDV-like viruses can protectrabbits against severe RHDV infection. For management ofrabbits in Australia and New Zealand, this would provide abasis for developing a strategy for enhancing the impact ofRHDV in areas of high rainfall. Field experiments should alsobe initiated to establish whether using conventional rabbitcontrol methods might further enhance the effectiveness ofRHDV or whether more virus could be released using baits fordistribution at strategic times. Clearly, if rabbit densitydetermines the outcome of RHDV outbreaks (8), then loweringrabbit numbers by poisoning and warren ripping would be alogical step towards making RHDV more effective. In wetterareas, RHDV alone has not always reduced rabbit numbers.Nonetheless, the virus may well prevent or retard the recoveryof populations after other control methods have reducednumbers of rabbits.

In Europe, enhancement of rabbit populations by managementof predators, re-stocking of areas where rabbits have declined,or immunising rabbits to enhance the breeding populationshould arguably be obvious objectives. The approach appearsfeasible given the hypothesis that dense rabbit populations canmaintain themselves.

Possibly the most interesting aspect of investigations of RHDhas been the consistency of patterns of epidemiology observedin Europe and in Australia. Some clear parallels exist, in thatRHD has had a greater impact on rabbits in arid areas than incooler, more humid regions. The underlying pattern of RHDepizootics in arid areas of Spain and Australia, where thedisease principally occurs among young adults in autumn orwinter, is also striking. These factors suggest that a very precisedescription of RHD is likely to be obtained when all currentfield studies are finally reported.

In conclusion, RHD appears set to become one of the betterdescribed viral diseases of the wild rabbit, rivallingmyxomatosis in terms of the understanding of theepidemiology of the disease. This should provide usefulcomparative information for considering the two diseases asinteracting pathogens and following the co-evolution of thediseases with the rabbit. Equally importantly, significantinsights should be obtained into the epidemiology of othercaliciviruses of veterinary or medical importance.


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Maladie hémorragique du lapin : épidémiologie de terrain etgestion des populations sauvages de lapins

B.D. Cooke

RésuméLa maladie hémorragique du lapin s’est établie parmi les populations de lapinssauvages d’Europe occidentale, d’Australie et de Nouvelle-Zélande. Le nombrede lapins sauvages a de ce fait considérablement diminué, surtout dans lesrégions arides d’Espagne, à l’intérieur des terres en Australie et dans l’île du Sudde Nouvelle-Zélande. Une connaissance approfondie de l’épidémiologie de cettemaladie est indispensable pour mieux la maîtriser chez les lapins sauvages, quece soit à des fins de repeuplement ou de contrôle des populations. Lorsque lamaladie a atteint des populations de lapins sauvages précédemment indemnes,

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les études épidémiologiques ont apporté de précieuses informations sur lerythme de la propagation, sur le rôle possible des insectes en tant que vecteursainsi que sur la corrélation entre l’impact de la maladie et les variablesclimatiques. Les recherches actuelles révèlent un même profil épidémiologiqueen Europe et en Australasie. De manière générale, les épizooties les plus gravesde maladie hémorragique du lapin se produisent chez de jeunes animaux quin’ont pas encore atteint l’âge adulte, ne possèdent plus d’anticorps maternels etont perdu la faculté de récupération liée à l’âge. Cependant, l’apparition desfoyers coïncide avec des variables climatiques qui déterminent la saison de lareproduction chez le lapin et favorisent les périodes de plus grande persistanceet propagation du virus causal. D’autres facteurs sont susceptibles de compliquer l’épidémiologie de la maladie,notamment la possibilité que des virus non pathogènes similaires à celui de lamaladie hémorragique du lapin soient présents dans les populations de lapinssauvages. De plus, la question de la survie du virus d’une année sur l’autre n’atoujours pas été élucidée, l’une des possibilités étant le portage asymptomatique.La compréhension de l’épidémiologie de la maladie hémorragique du lapin estdésormais suffisamment avancée pour envisager de manipuler les populations delapins afin de modifier le profil épidémiologique de la maladie et d’accentuer ouau contraire de réduire la mortalité qui lui est associée. Une telle modification del’épidémiologie de la maladie hémorragique du lapin pourrait permettre unemeilleure gestion des populations de lapins sauvages, à des fins de conservationde l’espèce ou de lutte contre les nuisibles.

Mots-clésCalicivirus – Épidémiologie – Faune sauvage – Lapins – Maladie hémorragique du lapin –Prophylaxie.�

Enfermedad hemorrágica del conejo: epidemiología sobre elterreno y gestión de las poblaciones de conejos salvajes

B.D. Cooke

ResumenLa enfermedad hemorrágica del conejo se ha afianzado en poblaciones deconejos salvajes de Europa Occidental, Australia y Nueva Zelanda. El número deejemplares salvajes ha experimentado un notable descenso, especialmente enlas zonas secas del Sur de España, la Australia continental y la Isla del Sur deNueva Zelanda. Para gestionar la enfermedad en las poblaciones salvajes, ya seacon fines de repoblación o de control demográfico, es fundamental conocer endetalle su epidemiología. Cuando la enfermedad empezó a propagarse entreconejos salvajes no expuestos previamente a ella, los estudios epidemiológicosproporcionaron datos de gran valor sobre la dinámica de propagación, la posibleintervención de insectos como vectores de transmisión y la correlación entre unaserie de variables climáticas y la incidencia de la enfermedad en las poblaciones.Las investigaciones actuales ponen de manifiesto un mismo patrónepidemiológico en Europa y Australasia. Por regla general, las epizootias másdevastadoras se registran entre jóvenes subadultos que han perdido losanticuerpos maternos y el poder de recuperación ligado a la edad. Sin embargo,la pauta temporal de esos brotes traduce variables climáticas que determinan la

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época de cría de los conejos y los periodos en que el virus de la enfermedad tienemás probabilidades de persistir y extenderse. Hay otros factores que pueden complicar la epidemiología, como la posibilidadde que las poblaciones de conejos salvajes alberguen virus no patógenos afinesal agente etiológico de la enfermedad. Queda por desentrañar además la formaen que el virus logra persistir de un año al siguiente, aunque se sabe que quizá lohaga en el interior de conejos portadores. Hoy en día se conoce suficientementela epidemiología de la enfermedad como para considerar la posibilidad demanipular poblaciones de conejos para modificar las pautas epidemiológicas ymaximizar o minimizar así la mortalidad causada por la enfermedad. Ello ayudaríaa gestionar las poblaciones de conejos salvajes, ya fuera con la idea deprotegerlas o de luchar contra la plaga en que a veces se convierten.

Palabras claveCalicivirus – Conejo – Control – Enfermedad hemorrágica del conejo – Epidemiología –Fauna salvaje.�

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